Control of the B Cell-Intrinsic Tolerance Programs by Ubiquitin Ligases Cbl and Cbl-b

Kitaura, Yasuyuki; Jang, Ihn Kyung; Wang, Yan; Han, Yoon Chi; Inazu, Tetsuya; Cadera, Emily J.; Schlissel, Mark S.; Hardy, Richard R.; Gu, Hua

doi:10.1016/j.immuni.2007.03.015

Cited by 113 publications

(137 citation statements)

References 55 publications

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“…Both our data and recently published observations (38) indicate that Ig␣ is a substrate for ubiquitinylation by Cbl. However, the delayed kinetics and low level of Ig␣ ubiquitinylation suggest that this ubiquitinylation event does not play a role in BCR endocytic trafficking.…”

Section: Discussionsupporting

confidence: 90%

Ubiquitinylation of Igβ Dictates the Endocytic Fate of the B Cell Antigen Receptor

Zhang

Veselits

O'Neill

et al. 2007

The Journal of Immunology

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In both infection and autoimmunity, the development of high-affinity Abs and memory requires B cells to efficiently capture and process Ags for presentation to cognate T cells. Although a great deal is known about how Ags are processed, the molecular mechanisms by which the BCR captures Ag for processing are still obscure. In this study, we demonstrate that the Igβ component of the BCR is diubiquitinylated and that this is dependent on the E3 ligase Itch. Itch−/− B lymphocytes manifest both a defect in ligand-induced BCR internalization and endocytic trafficking to late endosomal Ag-processing compartments. In contrast, analysis of ubiquitinylation-defective receptors demonstrated that the attachment of ubiquitins to Igβ is required for endosomal sorting and for the presentation of Ag to T cells, yet, ubiquitinylation is dispensable for receptor internalization. Membrane-bound Igμ was not detectably ubiquitinylated nor were the conserved lysines in the mu cytosolic tail required for trafficking to late endosomes. These results demonstrate that ubiquitinylation of a singular substrate, Igβ, is required for a specific receptor trafficking event. However, they also reveal that E3 ligases play a broader role in multiple processes that determine the fate of Ag-engaged BCR complexes.

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Section: Discussionsupporting

confidence: 90%

Ubiquitinylation of Igβ Dictates the Endocytic Fate of the B Cell Antigen Receptor

Zhang

Veselits

O'Neill

et al. 2007

The Journal of Immunology

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“…4). This observation may, however, reflect the fact that arrest of Cbl activity, in other cells, prompts phosphorylation of a similar array of proteins absent change in Syk quantity (23). Thus, cytokine-or integrin-induced Cbl binding to Syk may immediately impact the transport and/or association of the latter with other proteins, prior to its degradation.…”

Section: Y317fmentioning

confidence: 99%

“…In other cell types, Cbl is also a negative regulator of receptor and nonreceptor tyrosine kinases, as it promotes their degradation (22). OCs and their precursors express c-Cbl and another family member Cbl-b that compensates for the absence of c-Cbl (23,24). As combined deletion of both isoforms eventuates in early embryonic lethality (24), it is not clear if c-Cbl functions as an E3 ubiquitin ligase in OCs.…”

Section: Ocsmentioning

confidence: 99%

Syk Tyrosine 317 Negatively Regulates Osteoclast Function via the Ubiquitin-Protein Isopeptide Ligase Activity of Cbl

Zou¹,

Reeve

Zhao³

et al. 2009

Journal of Biological Chemistry

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Cytoskeletal organization of the osteoclast (OC), which is central to the capacity of the cell to resorb bone, is induced by occupancy of the ␣v␤3 integrin or the macrophage colony-stimulating factor (M-CSF) receptor c-Fms. In both circumstances, the tyrosine kinase Syk is an essential signaling intermediary. OCs2 are multinucleated cells generated by fusion of mononuclear progenitors of the monocyte/macrophage family under the aegis of M-CSF and receptor activator of nuclear factor B ligand (RANKL) (1). Upon mineralized matrix recognition, the OC polarizes its fibrillar actin, eventuating in the formation of an acidified extracellular microenvironment that degrades bone. Failure to undergo this polarization event results in OC hypo-function and consequently in varying degrees of osteopetrosis (2).Integrins are transmembrane ␣/␤ heterodimers that mediate cell-cell and cell-matrix interactions and generate intracellular signals when occupied by ligands (3). The integrin, ␣v␤3, is expressed by OCs, and binding of this complex to bone is pivotal to the resorptive process (4).M-CSF recognizes its transmembrane receptor tyrosine kinase, c-Fms, and induces receptor autophosphorylation at seven tyrosine residues within the cytoplasmic domain (5). Several Src homology-2 domain-containing molecules are recruited to the phosphotyrosine residues upon M-CSF binding and initiate signaling cascades that lead to cytoskeletal organization, survival, and proliferation of OC lineage cells (5-7). Both the ␣v␤3 integrin and M-CSF are important regulators of OC actin remodeling (4,6,8).Syk is a 72-kDa nonreceptor tyrosine kinase, which mediates ␣v␤3-and c-Fms-induced OC cytoskeletal organization and function in a phosphorylation-dependent manner via a process involving activation of associated adaptor proteins, such as SLP-76 and Vav3 (9, 10). A number of Syk tyrosine residues undergo phosphorylation following engagement of the integrin and Fc␥ receptor in immune (11) Cbl is a 120-kDa protein that is tyrosine-phosphorylated following activation by growth factors, cytokines, and integrins. It has two distinct but related activities, serving both as an adaptor protein (17, 18) and E3 ubiquitin ligase (19, 20). Cbl functions principally as an adaptor in OCs by participating in signaling complexes that are important in the assembly and remodeling of the actin cytoskeleton (18,21). In other cell types, Cbl is also a negative regulator of receptor and nonreceptor tyrosine kinases, as it promotes their degradation (22). OCs and their precursors express c-Cbl and another family member Cbl-b that compensates for the absence of c-Cbl (23, 24). As combined deletion of both isoforms eventuates in early embryonic lethality (24), it is not clear if c-Cbl functions as an E3 ubiquitin ligase in OCs. We establish that c-Cbl, recognizing Syk Y317 , prompts the ubiquitination of the kinases thereby arresting activation of cytoskeleton-organizing molecules and thus OC function. The Cbl-Syk Y317 complex is therefore important in maintenance of normal ...

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“…A Unique Role for c-Cbl in BCR-mediated Antigen Processing and Presentation-Cbl-b and c-Cbl are two related ubiquitin ligases known to interact directly with the BCR signaling molecule Syk (23,32,33). These two RING finger-type E3 ubiquitin ligases are ϳ50% similar at the amino acid level and share a general overall domain structure (Fig.…”

Section: Syk Is Required For Antigen-induced Bcr Ubiquitination and Bmentioning

confidence: 99%

“…Two members of this family, c-Cbl and Cbl-b, which have distinct functions in B cells (21,22), interact with several BCR signaling molecules such as PLC␥2, BLNK, PI3 kinase, Lyn, Vav, and, most relevant to this report, Syk (21)(22)(23). Subsequent to ITAM binding, Syk is phosphorylated on tyrosine 323, which generates a binding site for c-Cbl (24).…”

mentioning

confidence: 99%

The Syk-binding Ubiquitin Ligase c-Cbl Mediates Signaling-dependent B Cell Receptor Ubiquitination and B Cell Receptor-mediated Antigen Processing and Presentation

Katkere

Rosa

Drake

2012

Journal of Biological Chemistry

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Background: c-Cbl associates with various signaling molecules to regulate diverse signaling networks via ubiquitination of receptors and/or protein tyrosine kinases. Results: c-Cbl drives ubiquitin-dependent Ag⅐BCR trafficking to MIIC and BCR-mediated antigen processing and presentation. Conclusion: c-Cbl directs BCR-mediated antigen processing and presentation. Significance: c-Cbl coordinates antigen-induced BCR signaling and rapid BCR-mediated antigen processing and presentation to drive a strong humoral immune response.

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Control of the B Cell-Intrinsic Tolerance Programs by Ubiquitin Ligases Cbl and Cbl-b

Cited by 113 publications

References 55 publications

Ubiquitinylation of Igβ Dictates the Endocytic Fate of the B Cell Antigen Receptor

Ubiquitinylation of Igβ Dictates the Endocytic Fate of the B Cell Antigen Receptor

Syk Tyrosine 317 Negatively Regulates Osteoclast Function via the Ubiquitin-Protein Isopeptide Ligase Activity of Cbl

The Syk-binding Ubiquitin Ligase c-Cbl Mediates Signaling-dependent B Cell Receptor Ubiquitination and B Cell Receptor-mediated Antigen Processing and Presentation

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